Chemical compounds

ABSTRACT

This invention relates to novel compounds having the formula (I): and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C §371 ofInternational Application No. PCT1 GB2006/000522 (filed Feb. 15, 2006)which claims priority under 35 U.S.C. §119 (e) to U.S. ProvisionalApplication No. 60/653,330, filed on Feb. 16, 2005, and to U.S.Provisional Application No. 60/732,965, filed on Nov. 3, 2005.

FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods for the treatment andprevention of cancers and to the use of these pyrazole derivatives inthe manufacture of medicaments for use in the treatment and preventionof cancers.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases (RTK's) are a sub-family of protein kinasesthat play a critical role in cell signalling and are involved in avariety of cancer related processes including cell proliferation,survival, angiogenesis and metastasis. Currently up to 100 differentRTK's including tropomyosin-related kinases (Trk's) have beenidentified.

Trk's are the high affinity receptors activated by a group of solublegrowth factors called neurotrophins (NT). The Trk receptor family hasthree members—TrkA, TrkB and TrkC. Among the NTs there are (i) nervegrowth factor (NGF) which activates TrkA, (ii) brain-derived growthfactor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 whichactivates TrkC. Each Trk receptor contains an extra-cellular domain(ligand binding), a trans-membrane region and an intra-cellular domain(including kinase domain). Upon binding of the ligand, the kinasecatalyzes auto-phosphorylation and triggers downstream signaltransduction pathways.

Trk's are widely expressed in neuronal tissue during its developmentwhere Trk's are critical for the maintenance and survival of thesecells. A post-embryonic role for the Trk/neurotrophin axis (or pathway),however, remains in question. There are reports showing that Trk's playimportant role in both development and function of the nervous system(Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11,272-280).

In the past decade, a considerable number of literature documentationslinking Trk signalling with cancer have published. For example, whileTrk's are expressed at low levels outside the nervous system in theadult, Trk expression is increased in late stage prostate cancers. Bothnormal prostate tissue and androgen-dependent prostate tumours expresslow levels of Trk A and undetectable levels of Trk B and C. However, allisoforms of Trk receptors as well as their cognate ligands areup-regulated in late stage, androgen-independent prostate cancer. Thereis additional evidence that these late stage prostate cancer cellsbecome dependent on the Trk/neurotrophin axis for their survival.Therefore, Trk inhibitors may yield a class of apoptosis-inducing agentsspecific for androgen-independent prostate cancer (Weeraratna, A. T. etal The Prostate, 2000, 45, 140-148).

Furthermore, very recent literature also shows that over-expression,activation, amplification and/or mutation of Trk's are associated withsecretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectalcancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer(Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259).

There are a few reports of selective Trk tyrosine kinase inhibitors.Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research,1999, 59, 2395-2341) and other indolocarbazole analogues (WO0114380) asTrk inhibitors. It was shown that CEP-701 and/or CEP751, when combinedwith surgically or chemically induced androgen ablation, offered betterefficacy compared with mono-therapy alone. GlaxoSmithKline disclosedcertain oxindole compounds as Trk A inhibitors in WO0220479 andWO0220513. Recently, Japan Tobacco reported pyrazolyl condensed cycliccompounds as Trk inhibitors (JP2003231687A).

In addition to the above, Vertex Pharmaceuticals have described pyrazolecompounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789,WO03027111 and WO200437814; and AstraZeneca have reported pyrazolecompounds as inhibitors against IGF-1 receptor kinase (WO0348133).

SUMMARY OF THE INVENTION

In accordance with the present invention, the applicants have herebydiscovered novel pyrazole compounds, or pharmaceutically acceptablesalts thereof, which possess Trk kinase inhibitory activity and areaccordingly useful for their anti-proliferation and/or proapoptotic(such as anti-cancer) activity and in methods of treatment of the humanor animal body. The invention also relates to processes for themanufacture of said pyrazole compounds, or pharmaceutically acceptablesalts thereof, to pharmaceutical compositions containing them and totheir use in the manufacture of medicaments for use in the production ofan anti-proliferation and/or proapoptotic effect in warm-blooded animalssuch as man.

Also in accordance with the present invention the applicants providemethods of using such pyrazole compounds, or pharmaceutically acceptablesalts thereof, in the treatment of cancer.

The properties of the compounds claimed in this invention are expectedto be of value in the treatment of disease states associated with cellproliferation such as cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Furthermore, the compounds, or pharmaceutically acceptable saltsthereof, of the invention are expected to be of value in the treatmentor prophylaxis of cancers selected from congenital fibrosarcoma,mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acutelymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer,myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma,neuroblastoma, Kaposis sarcoma, ovarian cancer, breast cancer includingsecretory breast cancer, colorectal cancer, prostate cancer includinghormone refractory prostate cancer, bladder cancer, melanoma, lungcancer—non small cell lung cancer (NSCLC), and small cell lung cancer(SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma,thyroid cancer including papillary thyroid cancer, mesothelioma andleukaemia; particularly ovarian cancer, breast cancer, colorectalcancer, prostate cancer and lung cancer—NSCLC and SCLC; moreparticularly prostate cancer; and more particularly hormone refractoryprostate cancer.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ and R² are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁷; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁸;

X¹, X² and X³ are independently ═N— or ═CR⁹—;

R³ and R⁹ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹—; whereinR³ and R⁹ independently of each other may be optionally substituted oncarbon by one or more R²; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹³;

R⁴ and R⁵ are independently selected from hydrogen, halo, nitro, cyano,hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ and R⁵independently of each other may be optionally substituted on carbon byone or more R¹⁴; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁵;

A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylene may beoptionally substituted by one or more R¹⁶;

Ring C is carbocyclyl or heterocyclyl; wherein if said heterocyclylcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from R¹⁷;

R⁶ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁶ may be optionally substituted on carbon by oneor more R¹⁸; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR¹⁹;

n is 0, 1, 2 or 3; wherein the values of R⁶ may be the same ordifferent;

R⁷, R¹², R¹⁴, R¹⁶ and R¹⁸ and are independently selected from halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂-amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂-carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁰— or heterocyclyl-R²¹—; whereinR⁷, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may be optionallysubstituted on carbon by one or more R²²; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²³;

R⁸, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²³ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁸, R¹³, R¹⁵,R¹⁷, R¹⁹ and R²³ independently of each other may be optionallysubstituted on carbon by on or more R²⁴;

R²² and R²⁴ are independently selected from halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R²² andR²⁴ independently of each other may be optionally substituted on carbonby one or more R²⁵; and wherein if said heterocyclyl contains an—NH-moiety that nitrogen may be optionally substituted by a groupselected from R²⁶;

R¹⁰, R¹¹, R²⁰ and R²¹ are independently selected from a direct bond,—O—, —N(R²⁷)—, —C(O)—, —N(R²⁸)C(O)—, —C(O)N(R²⁹)—, —S(O)_(s)—,—SO₂N(R³⁰)— or —N(R³¹)SO₂—; wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ areindependently selected from hydrogen or C₁₋₆alkyl and s is 0-2;

R²⁵ is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy,trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl,methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino,ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl,ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl,N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and

R²⁶ is selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl;

or a pharmaceutically acceptable salt thereof.

Particular values of the variable groups contained in formula (I) are asfollows. Such values may be used, where appropriate, with any of thedefinitions, claims or embodiments defined hereinbefore or hereinafter.

R¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy or carbocyclyl.

R¹ is selected from methyl, t-butyl, isopropoxy or cyclopropyl.

R² is hydrogen.

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy or carbocyclyl.

R¹ and R² are independently selected from hydrogen, methyl, t-butyl,isopropoxy or cyclopropyl.

X³ is —N—; and X¹ and X² are independently ═CR⁹—.

X¹, X² and X³ are independently ═CR⁹—.

X¹ is ═CR⁹—; and X² and X³ are ═N—.

X² is ═CR⁹—; and X¹ and X³ are ═N—.

R³ and R⁹ are independently selected from hydrogen, halo, hydroxy andC₁₋₆alkyl.

R³ and R⁹ are independently selected from hydrogen, fluoro, chloro,hydroxy and methyl.

R⁴ and R⁵ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁴ and R⁵ independently of each other may be optionally substituted oncarbon by one or more R¹⁴; wherein R¹⁴ is hydroxy.

R⁴ and R⁵ are independently selected from hydrogen or methyl; wherein R⁴and R⁵ independently of each other may be optionally substituted oncarbon by one or more R¹⁴; wherein R¹⁴ is hydroxy.

R⁴ and R⁵ are independently selected from hydrogen, methyl orhydroxymethyl.

A is a direct bond.

A is C₁₋₂alkylene; wherein said C₁₋₂alkylene may be optionallysubstituted by one or more R¹⁶.

Ring C is heterocyclyl; wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁷.

Ring C is carbocyclyl.

Ring C is phenyl.

Ring C is phenyl, pyridyl, pyrimidinyl, 1,3-benzodioxolyl or 1H-indolyl.

Ring C is phenyl, pyrid-2-yl, pyrimidin-2-yl, 1,3-benzodioxol-5-yl or1H-indol-3-yl.

Ring C is pyridyl.

Ring C is pyrid-2-yl.

Ring C is pyrimidinyl.

Ring C is pyrimidin-2-yl.

R⁶ is halo.

R⁶ is fluoro.

n is 0 or 1.

n is 1.

Ring C, R⁶ and n together form 4-fluorophenyl, 5-fluoropyrid-2-yl or5-fluoropyrimidin-2-yl.

Ring C, R⁶ and n together form 4-fluorophenyl.

Ring C, R⁶ and n together form 5-fluoropyrid-2-yl.

Ring C, R⁶ and n together form 5-fluoropyrimidin-2-yl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ and R² are independently selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy or carbocyclyl;

X¹, X² and X³ are independently ═N— or ═CR⁹—;

R³ and R⁹ are independently selected from hydrogen, halo, hydroxy andC₁₋₆alkyl;

R⁴ and R⁵ are independently selected from hydrogen or C₁₋₆alkyl; whereinR⁴ and R⁵ independently of each other may be optionally substituted oncarbon by one or more R¹⁴;

A is a direct bond;

Ring C is carbocyclyl;

R⁶ is halo;

n is 1; and

R¹⁴ is hydroxy;

or a pharmaceutically acceptable salt thereof.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted herein above) wherein:

R¹ is selected from methyl, t-butyl, isopropoxy or cyclopropyl;

R² is hydrogen;

X¹, X² and X³ are independently ═N— or ═CR⁹—;

R³ and R⁹ are independently selected from hydrogen, fluoro, chloro,hydroxy and methyl;

R⁴ and R⁵ are independently selected from hydrogen, methyl orhydroxymethyl;

A is a direct bond;

Ring C is phenyl;

R⁶ is fluoro; and

n is 1;

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable saltthereof.

In a further aspect of the invention there is provided a compound offormula (I) selected from Examples 6, 11, 14, 15, 16, 24, 26, 27, 28 or30 or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the inhibition of Trkactivity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the treatment or prophylaxisof cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment of cancer ina warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the manufacture of a medicament for use in the treatment orprophylaxis of cancers (solid tumors and leukemia), fibroproliferativeand differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for use in the production of ananti-proliferative effect.

In an additional embodiment the present invention provides a method ofinhibiting Trk activity comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment of cancer comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancer comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides a method forthe treatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In an additional embodiment the present invention provides a method ofproducing an anti-proliferative effect in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theinhibition of Trk activity.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancer.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in thetreatment or prophylaxis of cancers (solid tumors and leukemia),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

In an additional embodiment the present invention provides apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, diluent or excipient for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe inhibition of Trk activity.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment or prophylaxis of cancer.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment of cancer in a warm-blooded animal such as man.

In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment or prophylaxis of cancers (solid tumours andleukaemia), fibroproliferative and differentiative disorders, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation in a warm-bloodedanimal such as man.

In an additional embodiment the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use inthe production of an anti-proliferative effect.

In one embodiment where the inhibition of Trk activity is referred toparticularly this refers to the inhibition of Trk A activity.

In another embodiment where the inhibition of Trk activity is referredto particularly this refers to the inhibition of Trk B activity.

Where the treatment (or prophylaxis) of cancer is referred to,particularly it refers to the treatment (or prophylaxis) of congenitalfibrosarcoma, mesoblastic nephroma, mesothelioma, acute myeloblasticleukemia, acute lymphocytic leukemia, multiple myeloma, melanoma,oesophageal cancer, myeloma, hepatocellular, pancreatic, cervicalcancer, Ewings sarcoma, neuroblastoma, Kaposis sarcoma, ovarian cancer,breast cancer including secretory breast cancer, colorectal cancer,prostate cancer including hormone refractory prostate cancer, bladdercancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), andsmall cell lung cancer (SCLC), gastric cancer, head and neck cancer,renal cancer, lymphoma, thyroid cancer including papillary thyroidcancer, mesothelioma, leukaemia, tumours of the central and peripheralnervous system, melanoma, fibrosarcoma including congenital fibrosarcomaand osteosarcoma. More particularly it refers to prostate cancer. Inaddition, more particularly it refers to SCLC, NSCLC, colorectal cancer,ovarian cancer and/or breast cancer. In a further aspect it refers tohormone refractory prostate cancer.

In a further aspect of the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof which process (wherein variable groups are, unlessotherwise specified, as defined in formula (I)) comprises of:

Process a) reaction of a compound of formula (II):

wherein Pg is a nitrogen protecting group; with a compound of formula(III):

wherein L is a displaceable group;Process b) for compounds of formula (I) wherein R⁴ is hydroxymethyl andR⁵ is hydrogen; reaction of a compound of formula (II) with an epoxideof formula (IV):

Process c) for compounds of formula (I) wherein X¹ is ═CR⁹—; reacting acompound of formula (V):

with a compound of formula (VI):

Process d) for compounds of formula (I) wherein X¹ is ═N—; reacting acompound of formula (V) with aqueous NaNO₂ solution;Process e) reacting a compound of formula (VII):

wherein L is a displaceable group; with an amine of formula (VIII):

wherein Pg is a nitrogen protecting group;Process f) reacting a compound of formula (IX):

with a compound of formula (X):

wherein L is a displaceable group;and thereafter if necessary:i) converting a compound of the formula (I) into another compound of theformula (I);ii) removing any protecting groups;iii) forming a pharmaceutically acceptable salt.

L is a displaceable group, suitable values for L are for example, a haloor sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxyor toluene-4-sulphonyloxy group.

Pg is a nitrogen protecting group. Suitable values for Pg are describedherein below.

Specific reaction conditions for the above reactions are as follows.

Process a) Compounds of formula (II) and (III) may be reacted togetherunder standard nucleophilic addition reactions for example in thepresence of a suitable base such as potassium carbonate and a suitablesolvent such as DMF and at a temperature in the range from 25 to 10° C.

Compounds of the formula (II) may be prepared according to Scheme 1:

wherein L is a displaceable group as defined herein above.

Compounds of formula (III) and (IIa) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process b) Compounds of formula (II) and (IV) may be reacted togetherunder epoxide ring opening reaction conditions for example in thepresence of a suitable catalyst such as LiClO₄, NaClO₄, Mg(ClO₄)₂ and asuitable solvent such as CH₃CN and at a temperature in the range from 25to 80° C.

Compounds of formula (IV) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process c) Compounds of formula (V) and compounds of formula (VI) may bereacted together in a suitable solvent such as ethanol at refluxtemperature.

Compounds (V) may be prepared according to Scheme 2:

wherein L is a displaceable group and Pg is a nitrogen protecting groupas defined herein above.

Compounds of formula (Va), (Vc) and (VI) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Process d) Compounds of formula (V) and an aqueous NaNO₂ solution may bereacted together in aqueous acetic acid.

Process e) Compounds of formula (VII) and (VIII) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (VII) wherein X¹ is selected from ═CR⁹— may beprepared according to Scheme 3:

wherein L is a displaceable group as defined herein above.

Compounds of formula (VII) wherein X¹ is selected from ═CR⁹— and R⁹ ishydroxy may be prepared according to Scheme 4:

wherein L is a displaceable group as defined herein above.

Compounds of formula (VII) wherein X¹ is selected from ═N— may beprepared according to Scheme 5:

wherein L is a displaceable group as defined herein above.

Compounds of the formula (VIII) are commercially available compounds, orthey are known in the literature, or they are prepared by standardprocesses known in the art.

Process f) Compounds of formula (IX) and (X) may be reacted togetherunder the conditions listed in Process a).

Compounds of formula (IX) may be prepared according to Scheme 6:

wherein L is a displaceable group as defined herein above.

Compounds of the formula (IXa) and (X) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

Certain intermediates disclosed herein are novel as such they areprovided as a further feature of the invention.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

DEFINITIONS

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” and “C₁₋₄alkyl” include methyl, ethyl, propyl,isopropyl and t-butyl. However, references to individual alkyl groupssuch as ‘propyl’ are specific for the straight-chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched-chain version only. A similar conventionapplies to other radicals. The term “halo” refers to fluoro, chloro,bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 4-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)—, and a ring sulphur atom may beoptionally oxidised to form the S-oxides. Examples and suitable valuesof the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl,thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino,pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl,imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl,N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone,4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Further examplesand suitable values of the term “heterocyclyl” are morpholino,piperazinyl and pyrrolidinyl. In one aspect of the invention a“heterocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic ring containing 5 or 6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, it may, unless otherwisespecified, be carbon or nitrogen linked, a —CH₂— group can optionally bereplaced by a —C(O)— and a ring sulphur atom may be optionally oxidisedto form the S-oxides.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Particularly “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.

The term “C_(m-n)” or “C_(m-n) group” used alone or as a prefix, refersto any group having m to n carbon atoms.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

An example of “C₁₋₆alkanoyloxy” is acetoxy. Examples of“C₁₋₆alkoxycarbonyl” include C₁₋₄alkoxycarbonyl, methoxycarbonyl,ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C₁₋₆alkoxy”include C₁₋₄alkoxy, C₁₋₃alkoxy, methoxy, ethoxy and propoxy. Examples of“C₁₋₆alkoxyimino” include C₁₋₄alkoxyimino, C₁₋₃alkoxyimino,methoxyimino, ethoxyimino and propoxyimino. Examples of“C₁₋₆alkanoylamino” include formamido, acetamido and propionylamino.Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2” includeC₁₋₄alkylsulphonyl, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, mesyl and ethylsulphonyl. Examples of “C₁₋₆alkylthio”include methylthio and ethylthio. Examples of “C₁₋₆alkylsulphonylamino”include methylsulphonylamino and ethylsulphsulphonylamino. Examples of“C₁₋₆alkanoyl” include C₁₋₄alkanoyl, propionyl and acetyl. Examples of“N—(C₁₋₆alkyl)amino” include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” include di-N-methylamino, di-(N-ethyl)amino andN-ethyl-N-methylamino. Examples of “C₂₋₆alkenyl” are vinyl, allyl and1-propenyl. Examples of “C₂₋₆alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” areN-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl andN-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)carbamoyl” areN—(C₁₋₄alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N—(C₁₋₆alkyl)₂carbamoyl” are N,N—(C₁₋₄alkyl)₂carbamoyl,dimethylaminocarbonyl and methylethylaminocarbonyl.

“RT” or “rt” means room temperature.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

It should be noted that the compounds claimed in this invention arecapable of existing in different resonance structures and thus thecompounds claimed herein include all possible resonance structures, forexample optical isomers, diastereoisomers and geometric isomers and alltautomeric forms of the compounds of the formula (I).

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms.

Formulations

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

An effective amount of a compound of the present invention for use intherapy of cancer is an amount sufficient to symptomatically relieve ina warm-blooded animal, particularly a human the symptoms of cancer, toslow the progression of cancer, or to reduce in patients with symptomsof cancer the risk of getting worse.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substance, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. Examples of such acidaddition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate,camphorsulfonate, choline, citrate, cyclohexyl sulfamate,diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate,hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate,nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate,diphosphate, picrate, pivalate, propionate, quinate, salicylate,stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), trifluoroacetate, and undecanoate. Base saltsinclude ammonium salts, alkali metal salts such as sodium, lithium andpotassium salts, alkaline earth metal salts such as aluminum, calciumand magnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, ornithine, and so forth. Also, basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl halides; aralkylhalides like benzyl bromide and others. Non-toxicphysiologically-acceptable salts are preferred, although other salts arealso useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

The term composition is intended to include the formulation of theactive component or a pharmaceutically acceptable salt with apharmaceutically acceptable carrier. For example this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition is divided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Combinations

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea);antitumour antibiotics (for example anthracyclines like adriamycin,bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere); and topoisomerase inhibitors (forexample epipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in International Patent ApplicationsWO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin α_(v)β₃ function and angiostatin);(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy;(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies; and(x) other treatment regimes including: dexamethasone, proteasomeinhibitors (including bortezomib), isotretinoin (13-cis retinoic acid),thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitorsCEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies,targeted radiation therapy with 131I-metaiodobenzylguanidine(131I-MIBG), anti-G(D2) monoclonal antibody therapy with or withoutgranulocyte-macrophage colony-stimulating factor (GM-CSF) followingchemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention, or pharmaceutically acceptable salts thereof, within thedosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

Synthesis

The compounds, or pharmaceutically acceptable salts thereof, of thepresent invention can be prepared in a number of ways well known to oneskilled in the art of organic synthesis. The compounds, orpharmaceutically acceptable salts thereof, of the present invention canbe synthesized using the methods described below, together withsynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as appreciated by those skilled in the art. Suchmethods include, but are not limited to, those described below. Allreferences cited herein are hereby incorporated in their entirety byreference.

The novel compounds, or pharmaceutically acceptable salts thereof, ofthis invention may be prepared using the reactions and techniquesdescribed herein. The reactions are performed in solvents appropriate tothe reagents and materials employed and are suitable for thetransformations being effected. Also, in the description of thesynthetic methods described below, it is to be understood that allproposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents, which are compatible with the reaction conditions,will be readily apparent to one skilled in the art and alternate methodsmust then be used.

EXAMPLES

The invention will now be further described with reference to thefollowing illustrative examples in which, unless stated otherwise:

-   -   (i) temperatures are given in degrees Celsius (° C.); operations        are carried out at room temperature or ambient temperature, that        is, in a range of 18-25° C.;    -   (ii) organic solutions were dried over anhydrous magnesium        sulfate; evaporation of organic solvent was carried out using a        rotary evaporator under reduced pressure (4.5-30 mmHg) with a        bath temperature of up to 60° C.;    -   (iii) chromatography means flash chromatography on silica gel;        thin layer chromatography (TLC) was carried out on silica gel        plates;    -   (iv) in general, the course of reactions was followed by TLC or        liquid chromatography/mass spectroscopy (LC/MS) and reaction        times are given for illustration only;    -   (v) final products have satisfactory proton nuclear magnetic        resonance (NMR) spectra and/or mass spectra data;    -   (vi) yields are given for illustration only and are not        necessarily those which can be obtained by diligent process        development; preparations were repeated if more material was        required;    -   (vii) when given, NMR data is in the form of delta values for        major diagnostic protons, given in part per million (ppm)        relative to tetramethylsilane (TMS) as an internal standard,        determined at 300 MHz in DMSO-d₆ unless otherwise stated;    -   (viii) chemical symbols have their usual meanings;    -   (ix) solvent ratio was given in volume:volume (v/v) terms.    -   (x) the following abbreviations have been used:        -   EtOAc ethyl acetate;        -   EtOH ethanol;        -   THF tetrahydrofuran;        -   DIEA diisopropylethylamine        -   DPPA diphenyl phosphorazidate;        -   MeOH methanol; and        -   DCM dichloromethane.

Example 1(2R)-2-{2-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-9H-purin-9-yl}-2-(4-fluorophenyl)ethanol

To a 25 ml round bottom flask was added palladium on activated carbon(10%, 104 mg, 0.098 mmol) and stirring bar. The flask was sealed,evacuated and refilled with hydrogen using balloon. A solution of(2R)-2-({2-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidin-4-yl}amino)-2-(4-fluorophenyl)ethanol(Method 1, 196 mg, 0.49 mmol) in EtOH/EtOAc (6 ml/1 ml) via syringe. Thereaction mixture was stirred at room temperature for 19 hours and wasfiltered through paper. The filtrate was concentrated to give a pinksolid. The solid was then dissolved in EtOH (4 ml) and to the mixturewas added formamidine acetate (100 mg, 0.96 mmol). The reaction mixturewas heated on heating block (70° C.) for 4 hours. Removal of solventfollowed by flash chromatography on silica gel (10-15% MeOH in EtOAc)gave the desired product as a solid (114 mg, 61% for two steps). NMR:0.63 (m, 2H), 0.93 (m, 2H), 1.86 (m, 1H), 4.04 (m, 1H), 4.38 (m, 1H),5.34 (m, 1H), 5.70 (m, 1H), 6.20 (m, 1H), 7.18 (m, 2H), 7.45 (m, 2H),8.45 (s, 1H), 8.73 (s, 1H), 9.48 (br s, 1H), 11.85 (br s, 1H).

Examples 2-5

Following a similar procedure to Example 1, the following compounds weresynthesized from a suitable pyrimidine by reacting it sequentially withH₂ and formamidine acetate.

Ex Compound NMR SM 2 N-(5-Cyclopropyl-1H- 0.63 (m, 2H), 0.91 (m, 2H),1.85 (m, 1H), Method 2 pyrazol-3-yl)-9-(4- 5.38 (s, 2H), 6.15 (s, 1H),7.17 (m, 2H), fluorobenzyl)-9H-purin- 7.42 (m, 2H), 8.33 (s, 1H), 8.75(s, 1H), 9.20 (br s, 2-amine 1H) 3 (2R)-2-(4-Fluoro 2.21 (s, 3H), 4.08(m, 1H), 4.37 (m, 1H), Method 3 phenyl)-2-{2-[(5- 5.37 (m, 1H), 5.69 (brs, 1H), 6.30 (s, 1H), methyl-1H-pyrazol-3- 7.18 (m, 2H), 7.44 (m, 2H),8.45 (s, 1H), 8.73 (s, yl)amino]-9H-purin-9- 1H), 9.81 (br s, 1H), 11.81(br s, 1H) yl}ethanol 4 N-(5-Cyclopropyl-1H- 0.64 (m, 2H), 0.92 (m, 2H),1.93 (m, 1H), Method 4 pyrazol-3-yl)-9-[(1S)-1- 1.94 (m, 3H), 5.80 (s,1H), 6.25 (s, 1H), (4-fluorophenyl)ethyl]- 7.17 (m, 2H), 7.42 (m, 2H),8.45 (s, 1H), 8.73 (s, 9H-purin-2-amine 1H), 9.49 (br s, 1H), 11.87 (brs, 1H) 5 9-[(1S)-1-(4-Fluoro 1.27 (m, 6H), 1.91 (m, 3H), 4.65 (m, 1H),Method 5 phenyl)ethyl]-N-(5- 5.36 (s, 1H), 6.10 (s, 1H), 7.17 (m, 2H),isopropoxy-1H-pyrazol- 7.43 (m, 2H), 8.52 (s, 1H), 8.81 (s, 1H), 10.11(br 3-yl)-9H-purin-2-amine s, 1H), 11.21 (br s, 1H)

Example 6(S)—N-(5-Cyclopronyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine

A mixture of(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine(Method 9; 0.260 g, 0.74 mmol) and formamidine acetate (0.123 g, 1.18mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to25° C., saturated NaHCO₃ solution (10 ml) and EtOAc (30 ml) were addedto the reaction mixture. The organic layer was separated, washed withbrine (10 ml), dried over Na₂SO₄, concentrated, and purified by columnchromatography (EtOAc:MeOH=40:1) to give the title compound as anoff-white solid (0.135 g, 50%). NMR (400 MHz) 11.78 (s, 1H), 9.23 (s,1H), 8.29 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.38 (m, 2H), 7.16 (m, 2H),6.90 (d, J=8.8 Hz, 1H), 6.21 (s, 1H), 5.84 (m, 1H), 1.95 (d, J=7.2 Hz,3H), 1.86 (m, 1H), 0.94 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 362. Found:[M+H]⁺ 363.

Example 7(S)-5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-3-(1-(4-fluorophenyl)ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

A mixture of crude(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine(Method 9; 0.100 g, 0.28 mmol) and carbodiimidazole (0.092 g, 0.57 mmol)in THF (5 ml) was stirred at 25° C. for 2 hours. The solvent was removedunder reduced pressure and the residue was purified by columnchromatography (EtOAc) to give the title compound as a white solid(0.083 g, 77%). NMR (400 MHz) 11.68 (s, 1H), 10.68 (s, 1H), 8.79 (br s,1H), 7.45 (m, 2H), 7.14 (m, 3H), 6.78 (d, J=8.8 Hz, 1H), 5.85 (s, 1H),5.63 (m, 1H), 1.94 (d, J=7.2 Hz, 3H), 1.80 (m, 1H), 0.87 (m, 2H), 0.56(m, 2H). MS: Calcd.: 378. Found: [M+H]⁺ 379.

Example 8(S)—N-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-2-methyl-3Himidazo[4,5-b]pyridin-5-amine

A mixture of crude(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine(Method 9; 0.120 g, 0.34 mmol) and acetamidine hydrochloride (0.052 g,0.55 mmol) in EtOH (5 ml) was heated at reflux overnight. After coolingto 25° C., saturated NaHCO₃ solution (10 ml) and EtOAc (30 ml) wereadded to the reaction mixture. The organic layer was separated, washedwith brine (10 ml), dried over Na₂SO₄, concentrated, and purified bychromatography (EtOAc:MeOH=100:1) to give the title compound as anoff-white solid (0.055 g, 43%). NMR (400 MHz, d⁶-Acetone) 11.14 (br s,1H), 8.44 (br s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.11 (m,2H), 7.00 (br s, 1H), 6.00 (m, 2H), 2.12 (s, 3H), 2.11 (d, J=7.2 Hz,3H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 376. Found: [M+H]⁺ 377.

Example 9-13

Following a similar procedure to Example 6 (or Example 8-Example 10),the following compounds were synthesized from a suitable pyridine byreacting it with formamidine acetate (or acetamidine hydrochloride inExample 10).

Ex Compound NMR/MS SM 9 3-(4-Fluorobenzyl)-N- (400 MHz) 11.79 (s, 1H),9.26 (s, 1H), 8.18 (s, Method (5-cyclopropyl-1H- 1H), 7.78 (d, J = 8.0Hz, 1H), 7.38 (m, 2H), 10 pyrazol-3-yl)-3H- 7.17 (m, 2H), 6.93 (br s,1H), 6.24 (s, 1H), imidazo[4,5-b]pyridin- 5.39 (s, 2H), 1.85 (m, 1H),0.92 (m, 2H), 5-amine 0.64 (m, 2H). MS: Calcd.: 348; Found: [M + H]⁺ 34910 3-(4-Fluorobenzyl)-N- (400 MHz) 11.74 (br s, 1H), 9.16 (br s, 1H),Method (5-cyclopropyl-1H- 7.16 (br s, 1H), 7.29 (m, 2H), 7.16 (m, 2H),10 pyrazol-3-yl)-2- 6.95 (br s, 1H), 6.18 (br s, 1H), 5.38 (br s, 2H),methyl-3H- 1.83 (m, 1H), 0.88 (m, 2H), 0.60 (m, 2H). MS:imidazo[4,5-b]pyridin- Calcd.: 362; Found: [M + H]⁺ 363 5-amine 11(R)-2-(5-(5- (400 MHz) 11.79 (s, 1H), 9.24 (br s, 1H), MethodCyclopropyl-1H- 8.33 (s, 1H), 7.78 (br s, 1H), 7.40 (m, 2H), 7.19 (m, 11pyrazol-3-ylamino)- 2H), 6.89 (br s, 2H), 6.21 (s, 1H), 5.73 (br s,3H-imidazo[4,5- 1H), 5.30 (s, 1H), 4.37 (m, 1H), 4.12 (m, 1H),b]pyridin-3-yl)-2-(4- 1.87 (m, 1H), 0.94 (m, 2H), 0.65 (m, 2H). MS:fluorophenyl)ethanol Calcd.: 378; Found: [M + H]⁺ 379 122-(5-[(5-Cyclopropyl- (400 MHz) 11.64 (s, 1H), 9.11 (s, 1H), 8.17 (s,Method 1H-pyrazol-3-yl)amino]- 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.10 (m,4H), 12 3H- 6.74 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 5.18 (brimidazo[4,5-b]pyridin- s, 2H), 4.39 (m, 4H), 1.75 (m, 1H), 0.89 (m,3-yl)-2-(4-fluoro 2H), 0.53 (m, 2H). MS: Calcd.: 408; Found:phenyl)propane-1,3- [M + H]⁺ 409 diol 13 (R)—N-(5- (400 MHz, CD₃OD) 8.22(s, 1H), 7.79 (d, J = 8.8 Hz, Method Cyclopropyl-1H- 1H), 7.40-7.36 (m,2H), 7.09-7.05 (m, 13 pyrazol-3-yl)-3-(1-(4- 2H), 6.78 (d, J = 8.8 Hz,1H), 5.94-5.89 (m, fluorophenyl)ethyl)- 1H), 2.00 (d, J = 7.0 Hz, 3H),1.91-1.87 (m, 3H-imidazo[4,5- 1H), 0.97-0.93 (m, 2H), 0.71-0.68 (m, 2H).b]pyridin-5-amine MS: Calcd.: 362; Found: [M + H]⁺ 363

Example 14(S)-6-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine

A mixture of(S)-5-chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine(Method 27; 0.300 g, 0.77 mmol) and formamidine acetate (0.129 g, 1.24mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to25° C., the reaction mixture was treated with saturated NaHCO₃ (10 ml)and EtOAc (30 ml). The organic layer was separated, washed with brine(10 ml), and dried over Na₂SO₄. The solvent was removed under reducedpressure and the residue was purified by column chromatography(EtOAc:MeOH=20:1) to give the title compound as an off-white solid(0.145 g, 47%). NMR (400 MHz) 11.96 (br s, 1H), 8.45 (s, 1H), 8.13 (brs, 1H), 8.12 (s, 1H), 7.36 (m, 2H), 7.16 (m, 1H), 6.18 (s, 1H), 5.87 (brs, 1H), 1.95 (d, J=6.8 Hz, 3H), 1.90 (m, 1H), 0.95 (m, 2H), 0.66 (m,2H). MS: Calcd.: 396. Found: [M+H]⁺ 397.

Example 15-18

Following a similar procedure to Example 14, the following compoundswere synthesized from a suitable aminopyridine by reacting it withformamidine acetate.

Ex Compound NMR/MS SM 15 (R)-2-(6-Chloro-5-(5- (400 MHz) 12.03 (s, 1H),8.45 (s, 1H), Method cyclopropyl-1H- 8.11 (s, 1H), 8.03 (br s, 1H), 7.38(m, 2H), 28 pyrazol-3-ylamino)-3H- 7.17 (m, 2H), 6.21 (s, 1H), 5.71 (brs, 1H), 5.29 (t, imidazo[4,5-b]pyridin- J = 5.2 Hz, 1H), 4.37 (m, 1H),4.08 (m, 1H), 3-yl)-2-(4- 1.89 (m, 1H), 0.96 (m, 2H), 0.65 (m, 2H).fluorophenyl)ethanol MS: Calcd.: 412; Found: [M + H]⁺ 413 16(R)-2-(6-Chloro-5-(5- (400 MHz) 11.95 (s, 1H), 8.46 (s, 1H), Methodmethyl-1H-pyrazol-3- 8.10 (s, 1H), 8.02 (br s, 1H), 7.40 (m, 2H), 29ylamino)-3H- 7.17 (m, 2H), 6.28 (s, 1H), 5.69 (br s, 1H), 5.32 (t,imidazo[4,5-b]pyridin- J = 4.8 Hz, 1H), 4.34 (m, 1H), 4.10 (m, 1H),3-yl)-2-(4- 2.26 (s, 3H). MS: Calcd.: 386; Found: fluorophenyl)ethanol[M + H]⁺ 387 17 (R)-2-(6-Chloro-5-(5- (400 MHz) 12.00 (s, 1H), 8.45 (s,1H), Method tert-butyl-1H-pyrazol-3- 8.11 (s, 1H), 8.04 (s, 1H), 7.39(m, 2H), 7.13 (m, 30 ylamino)-3H- 2H), 6.42 (s, 1H), 5.70 (m, 1H), 5.27(t, J = 4.8 Hz, imidazo[4,5-b]pyridin- 1H), 4.41 (m, 1H), 4.08 (m, 1H),3-yl)-2-(4- 1.28 (s, 9H). MS: Calcd.: 428; Found: [M + H]⁺fluorophenyl)ethanol 429 18 3-(4-Fluorobenzyl)-6- (400 MHz) 12.02 (s,1H), 8.33 (s, 1H), Method chloro-N-(5- 8.11 (s, 1H), 8.05 (s, 1H), 7.38(m, 2H), 7.17 (m, 31 cyclopropyl-1H- 2H), 6.28 (s, 1H), 5.40 (s, 2H),1.88 (m, 1H), pyrazol-3-yl)-3H- 0.94 (m, 2H), 0.64 (m, 2H). MS: Calcd.:382; imidazo[4,5-b]pyridin- Found: [M + H]⁺ 383 5-amine

Example 19(S)-5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-6-fluoro-3-(1-(4-fluorophenyl)ethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

A mixture of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinicacid (Method 40; 0.03 g, 0.08 mmol), triethylamine (0.02 g, 0.22 mmol),and DPPA (0.04 g, 0.15 mmol) in t-BuOH (2 ml) was heated to 83° C. for 5hours. The reaction was cooled, concentrated, and then dissolved in DCM(30 ml). The organic layer was washed with water (50×2 ml), dried,filtered, and concentrated. The resulting solid was purified by columnchromatography (DCM:MeOH=15:1) to give the title compounds (0.01 g,30%). NMR (400 MHz, CD₃OD) 7.48-7.44 (m, 2H), 7.24 (d, J=10.3 Hz, 1H),7.06-7.02 (m, 2H), 5.93 (br s, 1H), 5.76-5.71 (m, 1H), 1.99 (d, J=7.2Hz, 3H), 1.90-1.84 (m, 1H), 0.96-0.94 (m, 2H), 0.64-0.63 (m, 2H). MS:Calcd.: 396. Found: [M+H]⁺ 397.

Example 20(S)—N-(5-Cyclopropyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine

To a solution of(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine(Method 9; 0.08 g, 0.2 mmol), in aqueous acetic acid (5%, 3 ml) wasslowly added the aqueous NaNO₂ (0.01 g, 0.2 mmol, 1 ml H₂O) solution at25° C. The reaction was allowed to stir for an additional 5 minutes,then quenched with water (10 ml), and extracted with DCM (3×25 ml). Thecombined organic was washed with saturated NaHCO₃ (50 ml), dried,filtered, and concentrated. The resulting solid was purified by columnchromatography (DCM:MeOH=40:1) to give the title compound (0.037 g,50%). NMR (400 MHz, CD₃OD) 8.02 (d, J=8.9 Hz, 1H), 7.46-7.42 (m, 2H),7.08-7.04 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 6.23-6.19 (m, 2H), 2.12 (d,J=7.0 Hz, 3H), 1.95-1.91 (m, 1H), 1.02-1.00 (m, 2H), 0.75-0.72 (m, 2H).MS: Calcd.: 363. Found: [M+H]⁺ 364.

Example 21(S)—N-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-3-(1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine

A mixture of(S)-6-bromo-5-fluoro-1-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole(Method 44; 0.200 g, 0.59 mmol),5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tert-butyl ester(0.166 g, 0.741 mmol), Pd₂ dba₃ (0.011 g, 0.012 mmol), Xantphos (0.021g, 0.036 mmol), and Cs₂CO₃ (0.483 g, 1.48 mmol) in toluene (5 ml) washeated at reflux for 18 hrs. To this was added 10 ml of EtOAc andsaturated NH₄Cl solution (10 ml). The organic layer was separated,washed with brine (10 ml), dried over Na₂SO₄, and concentrated underreduced pressure. The resulted residue was dissolved in the mixture ofDCM:TFA (3:1 v/v, 4 ml), stirred at 25° C. for 2 hrs, concentrated, andtreated carefully with saturated NaHCO₃ solution (5 ml). The aqueouslayer was extracted with DCM (10 ml), dried over Na₂SO₄, concentratedunder reduced pressure, and purified by column chromatography (EtOAc) togive the title compound as a white solid (0.135 g, 60%). NMR (400 MHz)11.71 (br, 1H), 8.30 (s, 1H), 8.04 (rb, 1H), 7.91 (s, 1H), 7.40 (d, J=12Hz, 1H), 7.31 (m, 2H), 7.18 (m, 2H), 5.67 (m, 1H), 5.53 (s, 1H), 1.93(br, 3H), 1.84 (m, 1H), 0.92 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 379;Found: [M+H]⁺ 380.

Examples 22-23

Following a similar procedure to Example 21, the following compoundswere synthesized from a suitable benzimidazole and an aminopyrazole.

Ex Compound NMR/MS SM 22 (S)-6-Fluoro-3-(1-(4- (400 MHz) 11.67 (s, 1H),8.30 (s, 1H), Method fluorophenyl)ethyl)-N-(5- 8.08 (d, J = 7.6 Hz, 1H),7.93 (s, 1H), 7.39 (d, J = 12.0 Hz, 44 methyl-1H-pyrazol-3-yl)- 1H),7.32 (m, 2H), 7.18 (m, 2H), 3H-benzo[d]imidazol-5- 5.67 (q, J = 7.2 Hz,1H), 5.61 (s, 1H), amine 2.17 (s, 3H), 1.92 (d, J = 6.8 Hz, 3H). MS:Calcd.: 353; Found: [M + H]⁺ 354 23 (S)—N-(5-tert-Butyl-1H- (400 MHz)11.72 (s, 1H), 8.30 (s, 1H), Method pyrazol-3-yl)-6-fluoro-3- 8.11 (br,1H), 7.92 (s, 1H), 7.40 (d, J = 12 Hz, 44 (1-(4-fluorophenyl)ethyl)-1H), 7.31 (m, 2H), 7.17 (m, 2H), 5.69 (q, J = 6.8 Hz,3H-benzo[d]imidazol-5- 1H), 5.65 (s, 1H), 1.93 (d, J = 7.2 Hz, amine3H), 1.18 (s, 9H). MS: Calcd.: 395; Found: [M + H]⁺ 396

Example 24(S)-6-Fluoro-3-(1′-(4-fluorophenyl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine

To a solution of(S)-3-fluoro-N⁶-(1′-(4-fluorophenyl)ethyl)-N²-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine(Method 47, 0.6 g, 1.6 mmol) in a mixture of MeOH-THF (1:1, 40 ml) undernitrogen was added zinc dust (0.52 g, 8.0 mmol). A saturated aqueoussolution of NH₄Cl (4.0 ml) was then added slowly from an addition funnelover 20 minutes. Upon completion of the addition, the reaction wasallowed to stir for an additional 30 minutes, at which point a saturatedaqueous solution of NH₄OAc (5.0 ml) was added, and the reaction wasstirred for 30 minutes. EtOAc (15 ml) was then added, and the reactionwas stirred vigorously. The remaining solids were then filtered throughcelite, and the organic fraction was separated from the remainingfiltrate, dried over Na₂SO₄, filtered and concentrated to give to givecrude(S)-5-fluoro-N²-(1′-(4-fluorophenyl)ethyl)-N⁶-(5-methyl-1H-pyrazol-3-yl)pyridine-2,3,6-triamine(0.50 g, 90%) which was used without further purification. The aboveamine was immediately placed in EtOH (30 ml) and formamidine acetate(0.36 g, 3.4 mmol) was added. The reaction was flushed with nitrogen andheated to 95° C. for 12 hours. The reaction was cooled to roomtemperature, and a saturated aqueous NaHCO₃ solution (5 ml) was added,along with EtOAc (15 ml). The resulting mixture was stirred vigorouslyfor 10 minutes. The layers were then allowed to separate, and theorganic fraction was isolated, washed with brine (15 ml), dried overNa₂SO₄, filtered and concentrated. The resulting dark residue waspurified by column chromatography (hexanes-EtOAc=1:30) to give the titlecompound (0.30 g, 48%). ¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 7.57 (d,J=11.1 Hz, 1H), 7.46-7.42 (m, 2H), 7.04-7.00 (m, 2H), 6.29 (s, 1H),5.15-5.10 (m, 1H), 2.37 (s, 3H), 1.58 (d, J=7.0 Hz, 3H). MS: Calcd.:354. Found: [M+H]⁺ 355.

Examples 25-29

Following a similar procedure to Example 24, the following compoundswere synthesized from a suitable nitropyridine.

Ex Compound NMR/MS SM 25 N-(5-Cyclopropyl-1H- (400 MHz, CD₃OD) δ 8.31(s, 1H), 7.56 (d, J = 11.2 Hz, Method pyrazol-3-yl)-6-fluoro-3- 1H),7.40-7.37 (m, 2H), 48 (4-fluorobenzyl)-3H- 7.03-6.98 (m, 2H), 6.29 (s,1H), 4.61 (s, 2H), imidazo[4,5-b]pyridin-5- 1.98-1.90 (m, 1H), 1.05-1.01(m, 2H), 0.71-0.67 (m, amine 2H). MS: Calcd.: 366; Found: [M + H]⁺ 367.26 (R)-2-(5-(5-Cyclopropyl- (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.60 (d, J= 10.9 Hz, Method 1H-pyrazol-3-ylamino)- 1H), 7.48-7.44 (m, 2H), 496-fluoro-3H-imidazo[4,5- 7.07-7.03 (m, 2H), 6.18 (s, 1H), 5.12-5.09 (m,1H), b]pyridin-3-yl)-2-(4- 3.92-3.81 (m, 2H), 1.99-1.95 (m, 1H),fluorophenyl)ethanol 1.12-1.08 (m, 2H), 0.83-0.73 (m, 2H). MS: Calcd.:396; Found: [M + H]⁺ 397. 27 (S)—N-(5-Cyclopropyl- (400 MHz, CD₃OD) δ8.25 (s, 1H), 7.49 (d, J = 11.1 Hz, Method 1H-pyrazol-3-yl)-6- 1H),7.37-7.33 (m, 2H), 50 fluoro-3-(1-(4- 6.97-6.93 (m, 2H), 6.14 (s, 1H),5.05-5.02 (m, 1H), fluorophenyl)ethyl)-3H- 1.94-1.90 (m, 1H), 1.50 (d, J= 7.0 Hz, 3H), imidazo[4,5-b]pyridin-5- 1.05-1.01 (m, 2H), 0.77-0.67 (m,2H). MS: amine Calcd.: 380; Found: [M + H]⁺ 381. 28(S)-6-Fluoro-3-(1-(4- (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.57 (d, J = 11.1Hz, Method fluorophenyl)ethyl)-N-(5- 1H), 7.43-7.40 (m, 2H), 51isopropoxy-1H-pyrazol- 7.01-6.97 (m, 2H), 5.94 (s, 1H), 5.19-5.14 (m,1H), 3-yl)-3H-imidazo[4,5- 4.49-4.43 (s, 1H), 1.58 (d, J = 7.0 Hz, 3H),b]pyridin-5-amine 1.45-1.37 (m, 6H). MS: Calcd.: 398; Found: [M + H]⁺399. 29 (R)-2-(6-Fluoro-5-(5- (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.61 (d,J = 11.0 Hz, Method methyl-1H-pyrazol-3- 1H), 7.49-7.45 (m, 2H), 52ylamino)-3H- 7.08-7.04 (m, 2H), 6.23 (s, 1H), 5.10-5.07 (m, 1H),imidazo[4,5-b]pyridin-3- 3.91-3.79 (m, 2H), 2.36 (s, 3H). MS: Calcd.:yl)-2-(4- 370; Found: [M + H]⁺ 371. fluorophenyl)ethanol

Example 30(S)-6-Chloro-3-(1-(4-fluorophenyl)ethyl)-N-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine

(S)-5-Chloro-N²-(1-(4-fluorophenyl)ethyl)pyridine-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-2,3,6-triamine(Method 57, 0.31 g, 0.77 mmol) and formamidine acetate (0.16 g, 1.5mmol) in EtOH (5 ml) was heated at reflux overnight. Saturated sodiumbicarbonate solution (10 ml) and EtOAc (30 ml) was added. The organiclayer was separated, washed with brine (10 ml), and dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by chromatography (EtOAc-MeOH=40:1) to give the titlecompound as an off-white solid (0.065 g, 20%). ¹H NMR (400 MHz) δ 11.03(s, 1H), 9.03 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.37 (m, 2H), 7.14(m, 2H), 6.03 (m, 1H), 5.73 (s, 1H), 4.66 (m, 1H), 1.94 (d, J=6.8 Hz,3H), 1.28 (m, 6H). MS: Calcd.: 414. Found: [M+H]⁺ 415.

Example 31(S)-3-(1-(4-Fluorophenyl)ethyl)-N-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[415-b]pyridin-5-amine

(S)—N²-(1-(4-Fluorophenyl)ethyl)pyridine-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-2,3,6-triamine(Method 60, 0.27 g, 0.73 mmol) and formamidine acetate (0.15 g, 1.5mmol) in EtOH (5 ml) was heated at reflux overnight. Saturated sodiumbicarbonate solution (10 ml) and EtOAc (30 ml) was added. The organiclayer was separated, washed with brine (10 ml), and dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by chromatography (EtOAc-MeOH=40:1) to give the titlecompound as an off-white solid (0.058 g, 21%). ¹H NMR (400 MHz) δ 11.21(s, 1H), 9.75 (br s, 1H), 8.37 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.39 (m,2H), 7.16 (m, 2H), 6.70 (br s, 1H), 6.17 (br s, 1H), 5.34 (m, 1H), 4.67(m, 1H), 1.93 (d, J=7.2 Hz, 3H), 1.28 (m, 6H). MS: Calcd.: 371; Found:[M+H]⁺ 381.

Example 32(R)-2-(4-Fluorophenyl)-2-(5-(5-methyl-1H-pyrazol-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)ethanol

(R)-2-(3-Amino-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 62, 0.28 g, 0.82 mmol) and formamidine acetate (0.17 g, 1.6mmol) in EtOH (5 ml) was heated at reflux overnight. Saturated sodiumbicarbonate solution (10 ml) and EtOAc (30 ml) was added. The organiclayer was separated, washed with brine (10 ml) and dried over sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by chromatography (EtOAc-MeOH=40:1) to give the titlecompound as off white solid (0.021 g, 73%). ¹H NMR (400 MHz) δ 11.72 (s,1H), 9.24 (s, 1H), 8.33 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.40 (m, 2H),7.17 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 5.71 (br s, 1H),5.32 (t, J=4.2 Hz, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 4.03 (m, 1H), 2.22(s, 3H). MS: Calcd.: 352. Found: [M+H]⁺ 353.

Preparation of Starting Materials

Method 1

(2R)-2-({2-[(5-Cyclopronyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidin-4-yl}amino)-2-(4-fluorophenyl)ethanol

To a solution of(2R)-2-[(2-chloro-5-nitropyrimidin-4-yl)amino]-2-(4-fluorophenyl)ethanol(Method 6; 300 mg, 0.96 mmol) in EtOH (4 ml) was added a solution of5-cyclopropyl-1H-pyrazol-3-amine (118 mg, 0.96 mmol) in EtOH (2 ml) andtriethylamine (0.2 ml, 1.44 mmol). The reaction mixture was stirred at45° C. for 18 hours. Solvent was removed and the residue was dissolvedin EtOAc and was washed with water. The organic layer was concentrated.Flash chromatography on silica gel (EtOAc) gave the desired product as ayellowish solid (196 mg, 51%). NMR 0.64 (m, 2H), 0.92 (m, 2H), 1.83 (m,1H), 3.82 (m, 2H), 5.27 (m, 2H), 5.93 (m, 1H), 7.12 (m, 2H), 7.39 (m,2H), 8.95 (s, 1H), 9.19 (s, 1H), 10.54 (brs, 1H), 12.11 (brs, 1H).

Methods 2-5

Following a similar procedure to Method 1, the following compounds weresynthesized from a nitrochloropyrimidine by reacting it with an amine.

Method Compound NMR SM Amine 2 N²-(5-Cyclopropyl- 0.43 (m, 2H), 0.85 (m,2H), Method 7 5-cyclopropyl- 1H-pyrazol-3-yl)- 1.76 (m, 1H), 4.75 (m,2H), 1H-pyrazol-3- N⁴-(4- 5.94 (m, 1H), 7.13 (m, 2H), aminefluorobenzyl)-5- 7.33 (m, 2H), 8.94 (s, 1H), nitropyrimidine- 9.35 (s,1H), 10.51 (br s, 1H), 2,4-diamine 12.13 (br s, 1H) 3 (2R)-2-(4- 2.18(s, 3H), 3.80 (m, 2H), Method 6 5-methyl-1H- Fluorophenyl)-2- 5.26 (m,2H), 5.90 (m, 1H), pyrazol-3-amine ({2-[(5-methyl-1H- 7.15 (m, 2H), 7.43(m, 2H), pyrazol-3- 8.95 (s, 1H), 9.20 (s, 1H), yl)amino]-5- 10.5 (br s,1H), 12.06 (br s, 1H) nitropyrimidin-4- yl}amino)ethanol 4N²-(5-Cyclopropyl- (CDCl₃): 0.74 (m, 2H), Method 8 5-cyclopropyl-1H-pyrazol-3-yl)- 1.00 (m, 2H), 1.64 (m, 3H), 1H-pyrazol-3-N⁴-[(1S)-1-(4- 1.88 (m, 1H), 5.41 (m, 1H), amine fluorophenyl)ethyl]-6.12 (m, 1H), 7.02 (m, 2H), 5-nitropyrimidine- 7.33 (m, 2H), 8.85 (s,1H), 9.14 (s, 2,4-diamine 1H) 5 N⁴-[(1S)-1-(4- (CDCl₃): 1.25 (m, 6H),Method 8 5-isopropoxy- Fluorophenyl)ethyl]- 1.70 (m, 3H), 4.60 (m, 1H),1H-pyrazol-3- N²-(5-isopropoxy- 5.40 (m, 1H), 5.60 (m, 1H), amine1H-pyrazol-3-yl)-5- 7.02 (m, 2H), 7.33 (m, 2H), 8.80 (s,nitropyrimidine- 1H), 9.14 (s, 1H) 2,4-diamineMethod 6

(2R)-2-[(2-Chloro-5-nitropyrimidin-4-yl)amino]-2-(4-fluorophenyl)ethanol

To a solution of 2,4-dichloro-5-nitropyrimidine (1.5 g, 7.73 mmol) inEtOH (25 ml) at 0° C. was added triethylamine (1.6 ml, 11.6 mmol) and asolution of (2R)-2amino-2-(4-fluorophenyl)ethanol (prepared according toa procedure in J. Med. Chem. 1999, 42, 4981-5001, 1.2 g, 7.73 mmol). Thereaction mixture was stirred at 0° C. for 3 hours. The solvent wasremoved and the residue was dissolved in EtOAc and was washed withwater. The organic layer was concentrated. Flash chromatography onsilica gel (20-50% EtOAc in hexanes) gave the title compound as a solid(703 mg, 29%). NMR (CDCl₃) 4.00 (m, 2H), 5.50 (m, 1H), 7.07 (m, 2H),7.38 (m, 2H), 9.04 (s, 1H), 9.10 (br s, 1H).

Methods 7-8

Following a similar procedure to Method 6, the following compounds weresynthesized from a 2,4-dichloro-5-nitropyrimidine by reacting it with anamine.

Method Product NMR Amine 7 6-Chloro-N-(4- (CDCl₃): 4.82 (m, 2H), 7.05(m, (4- fluorobenzyl)-3- 2H), 7.37 (m, 2H), 8.59 (m, 1H),fluorobenzyl)amine nitropyridin-2-amine 9.08 (s, 1H) 86-Chloro-N-[(1S)-1-(4- (CDCl₃): 1.65 (m, 3H), 5.51 (m, [(1S)-1-(4-fluorophenyl)ethyl]-3- 1H), 7.05 (m, 2H), 7.37 (m, 2H),fluorophenyl)ethyl]amine nitropyridin-2-amine 8.59 (m, 1H), 9.03 (s, 1H)Method 9

(S)—N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine

To a suspension of(S)—N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)-3-nitropyridine-2,6-diamine(Method 14; 0.40 g, 1.05 mmol) and Zinc dust (0.342 g, 5.23 mmol) inMeOH:THF (1:1, 16 ml) was slowly added a saturated aqueous ammoniumchloride solution (2.5 ml). The mixture was stirred at 25° C. for 1hour, then treated with saturated ammonium acetate solution (4 ml). Theresulting mixture was stirred for another 30 minutes. Zn dust wasremoved by filtration and the cake was washed with EtOAc (20 ml). Theorganic layer was separated, washed with brine (10 ml), dried overNa₂SO₄, and concentrated. The crude product was used directly for thenext step without purification. MS: Calcd.: 352. Found: [M+H]⁺ 353.

Methods 10-13

Following a similar procedure to Method 9, the following compounds weresynthesized from a nitropyridine by reacting it with zinc dust.

Method Product MS SM 10 N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²- Calcd.:338; Found: Method 15 (4-fluorobenzyl)pyridine-2,3,6-triamine [M + H]⁺339 11 (2R)-2-({3-Amino-6-[(5-cyclopropyl-1H- Calcd.: 368; Found: Method16 pyrazol-3-yl)amino]pyridin-2-yl}amino)- [M + H]⁺ 3692-(4-fluorophenyl)ethanol 12 2-({3-Amino-6-[(5-cyclopropyl-1H-pyrazol-Calcd.: 398; Found: Method 17 3-yl)amino]pyridin-2-yl}amino)- [M + H]⁺399 2-(4-fluorophenyl)propane-1,3-diol 13N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²- Calcd.: 352; Found: Method 18[(1R)-1-(4-fluorophenyl)ethyl]pyridine- [M + H]⁺ 353 2,3,6-triamineMethod 14

(S)—N⁶-(5-Cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluoro-phenyl)ethyl)-3-nitropyridine-2,6-diamine

A mixture of(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method19; 1.74 g, 5.88 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.36mmol), and DIEA (1.28 ml, 7.36 mmol) in n-BuOH (10 ml) was heated in asealed tube at 160° C. for 60 hours. The solvent was removed underreduced pressure and the residue was purified by chromatography (hexane:EtOAc=1:1) to give the title compound as a yellow solid (1.35 g, 60%).NMR (400 MHz) 12.15 (s, 1H), 10.43 (br, 1H), 9.19 (br, 1H), 8.12 (d,J=9.2 Hz, 1H), 7.45 (m, 2H), 7.17 (m, 2H), 6.25 (br, 1H), 6.14 (br, 1H),5.45 (m, 1H), 1.87 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 0.95 (m, 2H), 0.65(m, 2H). MS: Calcd.: 382. Found: [M+H]⁺ 383.

Methods 15-18

Following a similar procedure to Method 14, the following compounds weresynthesized from a chloronitropyridine by reacting it with an amine.

Method Product NMR/MS Amine SM 15 N⁶-(5- (400 MHz,) 12.10 (br s, 1H), 5-Method Cyclopropyl- 10.40 (br s, 1H), 9.43 (br, 1H), 8.09 (d, J = 6.8Hz, cyclopropyl- 20 1H-pyrazol-3- 1H), 7.37 (m, 2H), 7.15 (m,1H-pyrazol-3- yl)-N²-(4- 2H), 6.24 (br s, 1H), 6.04 (br s, 1H), aminefluorobenzyl)- 4.80 (d, J = 5.6 Hz, 2H), 1.772 (m, 3-nitropyridine- 1H),0.85 (m, 2H), 0.46 (m, 2H). 2,6-diamine MS: Calcd.: 368; Found: [M + H]⁺369 16 (2R)-2-({6-[(5- (400 MHz) 12.10 (s, 1H), 10.39 (br 5- MethodCyclopropyl- s, 1H), 9.57 (br s, 1H), 8.11 (d, J = 9.2 Hz, cyclopropyl-21 1H-pyrazol-3- 1H), 7.28 (m, 2H), 7.15 (m, 1H-pyrazol-3- yl)amino]-3-2H), 6.23 (br s, 1H), 5.76 (s, 1H), amine nitropyridin-2- 5.35 (br s,1H), 5.19 (t, J = 4.8 Hz, yl}amino)-2-(4- 1H), 3.86 (m, 1H), 3.75 (m,1H), fluorophenyl)ethanol 1.87 (m, 1H), 0.95 (m, 2H), 0.64 (m, 2H). MS:Calcd.: 398; Found: [M + H]⁺ 399 17 2-({6-[(5- (400 MHz) 11.94 (s, 1H),10.15 (br 5- Method Cyclopropyl- s, 1H), 9.85 (s, 1H), 8.12 (d, J = 9.2Hz, cyclopropyl- 22 1H-pyrazol-3- 1H), 7.40 (m, 2H), 7.13 (m, 2H),1H-pyrazol-3- yl)amino]-3- 6.19 (br s, 1H), 2.86 (br s, 2H), aminenitropyridin-2- 4.44 (m, 4H), 1.65 (m, 1H), 0.87 (m, 2H),yl}amino)-2-(4- 0.47 (m, 2H). MS: Calcd.: 428; fluorophenyl)propane-Found: [M + H]⁺ 429. 1,3-diol 18 N⁶-(5- MS: Calcd.: 382; Found: [M + H]⁺5- Method Cyclopropyl- 383. cyclopropyl- 23 1H-pyrazol-3- 1H-pyrazol-3-yl)-N²-[(1R)-1- amine (4- fluorophenyl)ethyl]- 3- nitropyridine-2,6-diamineMethod 19

(S)-6-Chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) andpotassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH₃CN (20 ml), wasadded (S)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at0° C. The reaction mixture was stirred at 25° C. for 17 hours. The solidwas removed by filtration and the resulted cake was washed with EtOAc(20 ml). The combined filtrate was concentrated and purified by columnchromatography (hexane:EtOAc=10:1) to give the title compound as ayellow solid (1.74 g, 82%). NMR (400 MHz) 8.65 (d, J=7.6 Hz, 1H), 8.43(d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz, 1H),5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).

Methods 20-23

Following a similar procedure to Method 19, the following compounds weresynthesized from a 2,6-dichloro-3-nitropyridine by reacting it with anamine.

Method Product NMR/MS Amine 20 6-Chloro-N-(4- (400 MHz, CDCl₃) 8.58 (brs, (4-fluoro- fluorobenzyl)-3- 1H), 8.37 (d, J = 8.4 Hz, 1H),phenyl)methanamine nitropyridin-2-amine 7.36 (m, 2H), 7.04 (m, 2H), 6.67(d, J = 8.4 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H) 21 (2R)-2-[(6-Chloro-3-(400 MHz) 8.96 (d, J = 7.6 Hz, (R)-2-amino-2-(4-nitropyridin-2-yl)amino]- 1H), 8.46 (d, J = 8.4 Hz, 1H),fluorophenyl)ethanol 2-(4-fluorophenyl)ethanol 7.45 (m, 2H), 7.15 (m,2H), 6.81 (d, J = 8.8 Hz, 1H), 5.27 (m, 2H), 3.80 (m, 2H) 222-[(6-Chloro-3- (400 MHz) 9.13 (s, 1H), 8.44 (d, Method 24nitropyridin-2-yl)amino]- J = 8.4 Hz, 1H), 7.39 (m, 2H), 2-(4- 7.06 (m,2H), 6.73 (d, J = 8.8 Hz, fluorophenyl)propane-1,3- 1H), 5.16 (t, J =5.6 Hz, 2H), diol 4.07 (m 2H), 3.96 (m, 2H). MS: Calcd.: 341; Found:[M + H]⁺ 342 23 6-Chloro-N-[(1R)-1-(4- MS: Calcd.: 295; Found: [M + H]⁺(R)-1-(4- fluorophenyl)ethyl]-3- 296 fluorophenyl)ethanaminenitropyridin-2-amineMethod 24

2-Amino-2-(4-fluorophenyl)propane-1,3-diol

A suspension of 2-(4-fluorophenyl)-2-nitroproane-1,3-diol (Method 25;4.5 g, 20.9 mmol) and Raney nickel (0.45 g, 5.23 mmol) in MeOH (50 ml)was degassed and stirred under H₂ (48 psi) for 2 hours. The catalyst wasremoved by filtration. The filtrate was concentrated and recrystallizedfrom hexane:EtOAc (1:1) to give the title compound (2.35 g, 61%) as awhite solid. NMR (400 MHz) 7.55 (m, 2H), 7.07 (m, 2H), 4.65 (t, J=5.2Hz, 2H), 3.49 (m, 4H), 1.76 (s, 2H).

Method 25

2-(4-Fluorophenyl)-2-nitroproane-1,3-diol

To a solution of 1-fluoro-4-(nitromethyl)benzene (Method 26; 10.0 g, 80%pure; 52 mmol) and TEA (15.1 ml, 108.3 mmol) in dioxane (50 ml) wasadded formaldehyde (8.6 ml, 116 mmol) dropwise at 0° C. After addition,the reaction was slowly warmed up to 25° C. overnight. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (hexane:EtOAc=10:1) to give the title compound as a whitesolid (4.5 g, 41%). NMR (400 MHz) 7.41 (m, 2H), 7.22 (m, 2H), 5.39 (t,J=5.2 Hz, 2H), 4.22 (m, 4H).

Method 26

1-Fluoro-4-(nitromethyl)benzene

A mixture of 1-(bromomethyl)-4-fluorobenzene (11.52 g, 61 mmol) andAgNO₂ (11.3 g, 73 mmol) in benzene (200 ml) was stirred vigorously at25° C. for 25 hrs. The solid was removed by filtration and washed withdiethyl ether (500 ml). The combined organic was concentrated to givethe title compound (10.0 g, 80% pure; 85%) which was used withoutfurther purification. NMR (400 MHz, CDCl₃) 7.44 (m, 2H), 7.18 (m, 2H),5.42 (s, 2H).

Method 27

(S)-5-Chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine

To a suspension of(S)-3-chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamine(Method 32; 0.57 g, 1.37 mmol) and zinc dust (0.447 g, 6.84 mmol) inMeOH:THF (1:1, 24 ml) was slowly added saturated ammonium chloridesolution (3.5 ml). The reaction mixture was stirred at 25° C. for 2hours, followed by addition of saturated ammonium acetate solution (5ml). The resulting mixture was stirred for another 30 minutes. Zn dustwas removed by filtration and washed with EtOAc (20 ml). The organiclayer was separated, washed with brine (10 ml), and dried over Na₂SO₄.After removal of solvent, the crude product was used directly for thenext step without further purification. MS: Calcd.: 386. Found: [M+H]⁺387.

Methods 28-31

Following a similar procedure to Method 27, the following compounds weresynthesized from a nitropyridine by reacting it with zinc dust.

Method Product NMR/MS SM 28 (2R)-2-({3-Amino-5-chloro-6-[(5-cyclopropyl-MS: Calcd.: 402; Method 1H-pyrazol-3-yl)amino]pyridin-2-yl}amino)-2-Found: [M + H]⁺ 403 33 (4-fluorophenyl)ethanol 29(2R)-2-({3-Amino-5-chloro-6-[(5-methyl-1H- MS: Calcd.: 376; Methodpyrazol-3-yl)amino]pyridin-2-yl}amino)-2-(4- Found: [M + H]⁺ 377 34fluorophenyl)ethanol 30 (2R)-2-({3-Amino-6-[(5-tert-butyl-1H-pyrazol-3-MS: Calcd.: 418; Method yl)amino]-5-chloropyridin-2-yl}amino)-2-(4-Found: [M + H]⁺ 419 35 fluorophenyl)ethanol 315-Chloro-N⁶-(5-cyclopropyl-1H-pyrazol-3-yl)- MS: Calcd.: 372; MethodN²-(4-fluorobenzyl)pyridine-2,3,6-triamine Found: [M + H]⁺ 373 36Method 32

(S)-3-Chloro-N²-(5-cyclopropyl-1H-pyrazol-3-yl)-N⁶-(1-(4-fluorophenyl)ethyl)-5-nitropyridin-2,6-diamine

A mixture of(S)-5,6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine(Method 37; 0.61 g, 79% pure, 1.46 mmol),5-cyclopropyl-1H-pyrazol-3-amine (0.27 g, 2.19 mmol), and DIEA (0.38 ml,2.19 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 100° C. for48 hours. The solvent was removed under reduced pressure and the residuewas purified by column chromatography (hexane:EtOAc=2:1) to give thetitle compound as a yellow solid (0.57 g, 94%). NMR (400 MHz) 12.34 (s,1H), 9.34 (s, 1H), 8.93 (d, J=7.6 Hz, 1H), 8.26 (s, 1H), 7.32 (m, 2H),7.12 (m, 2H), 6.01 (s, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.56 (d, J=7.2Hz, 3H), 0.96 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 416. Found: [M+H]⁺ 417.

Methods 33-36

Following a similar procedure to Method 32, the following compounds weresynthesized from a chloronitropyridine by reacting it with an amine.

Method Product NMR/MS Amine SM 33 (2R)-2-({5-Chloro-6- (400 MHz) 12.28(s, 1H), 5- Method [(5-cyclopropyl-1H- 9.33 (d, J = 7.6 Hz, 1H), 9.28(s, cyclopropyl- 38 pyrazol-3-yl)amino]- 1H), 8.27 (s, 1H), 7.30 (m,1H-pyrazol-3- 3-nitropyridin-2- 2H), 7.13 (m, 1H), 5.94 (s, amineyl}amino)-2-(4- 1H), 5.22 (br s, 2H), fluorophenyl)ethanol 3.84-3.73 (m,2H), 1.90 (m, 1H), 0.97 (m, 2H), 0.68 (m, 2H). MS: Calcd.: 432; Found:[M + H]⁺ 433 34 (2R)-2-({5-Chloro-6- (400 MHz) 12.23 (s, 1H),5-methyl-1H- Method [(5-methyl-1H- 9.35 (d, J = 7.2 Hz, m), 9.30 (s,pyrazol-3- 38 pyrazol-3-yl)amino]- 1H), 8.27 (s, 1H), 7.32 (m amine3-nitropyridin-2- 2H), 7.14 (m, 2H), 5.86 (s, yl}amino)-2-(4- 1H), 5.23(t, J = 4.8 Hz, 1H), fluorophenyl)ethanol 5.18 (m, 1H), 3.81 (m, 1H),3.74 (m, 1H), 2.23 (s, 3H). MS: Calcd.: 406; Found: [M + H]⁺ 407 35(2R)-2-({6-[(5-tert- (400 MHz) 12.36 (s, 1H), 5-tert-butyl- MethodButyl-1H-pyrazol-3- 9.30 (s, 1H), 9.29 (d, J = 7.6 Hz, 1H-pyrazol-3- 38yl)amino]-5-chloro-3- 1H), 8.27 (s, 1H), 7.26 (m amine nitropyridin-2-2H), 7.08 (m, 2H), 6.18 (s, yl}amino)-2-(4- 1H), 5.29 (m, 1H), 5.21 (t,J = 4.8 Hz, fluorophenyl)ethanol 1H), 3.81 (m, 2H), 1.28 (s, 9H). MS:Calcd.: 448; Found: [M + H]⁺ 449 36 3-Chloro-N²-(5- (400 MHz) 12.33 (s,1H), (4- Method cyclopropyl-1H- 9.32 (br s, 1H), 8.26 (s, 1H),fluorophenyl)- 39 pyrazol-3-yl)-N⁶-(4- 8.20 (br s, 1H), 7.53 (m, 2H),methanamine fluorobenzyl)-5- 7.11 (m, 1H), 5.96 (s, 1H), 4.69 (d,nitropyridine-2,6- J = 6.0 Hz, 2H), 1.79 (m, 1H), diamine 0.87 (m, 2H),0.47 (m, 2H). sMS: Calcd.: 402; Found: [M + H]⁺ 403Method 37

(S)-5,6-Chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

To a mixture of 2,3,6-trichloro-5-nitropyridine (1.00 g, 4.40 mmol) andpotassium carbonate (0.79 g, 5.7 mmol) in anhydrous acetonitrile (10 ml)was added (S)-1-(4-fluoro-phenyl)-ethylamine (0.64 g, 4.62 mmol)dropwise at 0° C. After addition, the reaction mixture was stirred at25° C. for 17 hours. The solid was removed by filtration and washed withEtOAc (20 ml). After evaporation of the solvent, the resulted residuewas purified by column chromatography (hexane:EtOAc=10:1) to give thetitle compound as a yellow solid (0.61 g, 79% pure, 33%). NMR (400 MHz,CDCl₃) 8.46 (br s, 2H), 7.36 (m, 2H), 7.03 (m, 2H), 5.40 (m, 1H), 1.63(d, J=6.8 Hz, 3H).

Methods 38-39

Following a similar procedure to Method 37, the following compounds weresynthesized from a 2,3,6-trichloro-5-nitropyridine by reacting it withan amine.

Method Product NMR/MS Amine 38 (2R)-2-[(5,6-Dichloro-3- (400 MHz) 8.91(d, J = 7.2 Hz, (R)-2-amino-2- nitropyridin-2-yl)amino]-2- 1H), 8.66 (s,1H), 7.45 (m, 2H), (4-fluorophenyl)ethanol (4-fluorophenyl)ethanol 7.15(m, 2H), 5.25 (m, 2H), 3.80 (m, 2H) 39 3,6-Dichloro-N-(5- (400 MHz)12.37 (s, 1H), 5-cyclopropyl- cyclopropyl-1H-pyrazol-3- 9.83 (s, 1H),8.54 (s, 1H), 6.27 (s, 1H-pyrazol-3- yl)-5-nitropyridin-2-amine 1H),1.94 (m, 1H), 0.95 (m, 2H), amine 0.70 (m, 2H). MS: Calcd.: 313; Found:[M + H]⁺ 314Method 40

(S-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinicacid

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide(Method 41; 1.0 g, 2.5 mmol) was dissolved in a 10% aqueous EtOHsolution (10 ml) at 25° C., followed by addition of solid KOH (2.8 g,50.0 mmol). The reaction solution was heated to 95° C. for 4 days,cooled to 25° C., and extracted with DCM (2×50 ml). The aqueous layerwas then acidified to pH 3. The resulting solid (0.55 g), was collectedby filtration and dried under vacuum. MS: Calcd.: 399. Found: [M+H]⁺400.

Method 41

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide

To a solution of(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile(Method 42; 0.5 g, 1.3 mmol) in MeOH (50 ml) was added KOH solution(25%, 2 ml), followed by addition of H₂O₂ (30%, 0.1 ml). The resultingdark red solution was heated to 65° C. for 1 hour, cooled, andconcentrated. The resulting residue was dissolved in EtOAc (50 ml),washed with water (30 ml), dried, filtered, and concentrated. Theresulting solid was purified by column chromatography (DCM:MeOH=30:1) togive the title compound (0.30 g, 60%). MS: Calcd.: 398. Found: [M+H]⁺399.

Method 42

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile

A mixture of2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile(Method 43; 0.8 g, 2.8 mmol), (S)-1-(4-fluorophenyl)ethanamine (0.8 g,5.6 mmol), and DIEA (0.5 g, 3.7 mmol) in n-BuOH (4 ml) was heated in asealed tube at 140° C. for 48 hrs. The reaction mixture was concentratedand purified by column chromatography (DCM:MeOH=50:1) to give the titlecompound (0.55 g, 50%). MS: Calcd.: 380. Found: [M+H]⁺ 381.

Method 43

2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile

A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.9 g, 16.0 mmol) inCH₃CN (20 ml) was added dropwise to a solution of2,6-dichloro-5-fluoronicotinonitrile (3.0 g, 16.0 mmol) andtriethylamine (2.1 g, 20.0 mmol) in CH₃CN (80 ml) at 25° C. Theresulting solution was heated to 82° C. for 18 hrs, and then cooled to25° C. The resulted precipitate was collected by filtration and washedwith CH₃CN (100 ml) to give the title compound (3.2 g, 73%). MS: Calcd.:277. Found: [M+H]⁺ 278.

Method 44

(S)-6-Bromo-5-fluoro-1-(1-(4-fluorophenyl)ethyl)-1H-benzo[d]imidazole

A mixture of(S)-5-bromo-4-fluoro-N′-(1-(4-fluorophenyl)ethyl)benzene-1,2-diamine(Method 45; 0.62 g, 1.90 mmol) and formamidine acetate (0.316 g, 3.03mmol) in EtOH (5 ml) was heated at reflux for 5 hours. After cooling to25° C., the reaction mixture was treated with saturated sodiumbicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer wasseparated, washed with brine (10 ml), dried over Na₂SO₄, concentrated,and purified by column chromatography (hexane:EtOAc=1:5) to give thetitle compound as a white solid (0.522 g, 82%). NMR (400 MHz, CDCl₃)8.06 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 7.15 (m,2H), 7.06 (m, 2H), 5.54 (q, J=6.8 Hz, 1H), 1.98 (d, J=6.8 Hz, 3H). MS:Calcd.: 336. Found: [M+H]⁺ 337.

Method 45

(S)-5-Bromo-4-fluoro-N¹-(1-(4-fluorophenyl)ethyl)benzene-1,2-diamine

To a suspension of(S)-5-bromo-4-fluoro-N-(1-(4-fluorophenyl)ethyl)-2-nitrobenzenamine(Method 46; 0.63 g, 1.76 mmol) and zinc dust (0.554 g, 8.47 mmol) inMeOH:THF (1:1, 24 ml) was slowly added the saturated ammonium chloridesolution (4 ml). The reaction mixture was stirred at 25° C. for 2 hoursfollowed by addition of saturated ammonium acetate solution (5 ml). Theresulting mixture was stirred for another 30 minutes. Zn dust wasremoved by filtration and washed with EtOAc (20 ml). The organic layerwas separated, washed with brine (10 ml), dried over Na₂SO₄, andconcentrated under reduced pressure to give the crude product which wasdirectly used for the next step without further purification. MS:Calcd.: 326. Found: [M+H]⁺ 327.

Method 46

(S)-5-Bromo-4-fluoro-N-(1-(4-fluorophenyl)ethyl)-2-nitrobenzenamine

A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (0.464 g, 1.95 mmol),(S)-1-(4-fluoro-phenyl)-ethylamine (0.298 g, 2.14 mmol), and DIEA (0.41ml, 2.34 mmol) in n-BuOH (5 ml) was heated at 80° C. for 17 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography (hexane:EtOAc=5:1) to give the title compoundas a yellow solid (0.63 g, 96%). NMR (400 MHz, CDCl₃) 8.23 (br, 1H),7.95 (d, J=8.8 Hz, 1H), 7.29 (m, 2H), 7.08 (m, 2H), 6.84 (d, J=5.6 Hz,1H), 4.62 (m, 1H), 1.63 (d, J=6.8 Hz, 3H).

Method 47

(S)-3-Fluoro-N⁶-(1-(4-fluorophenyl)ethyl)-N²-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine

To a solution of(S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine(Method 53, 0.70 g, 2.3 mmol) in THF (12 ml) was added DIEA (0.39 g, 3.0mmol) and 5-methyl-1H-pyrazol-3-amine (0.45 g, 4.7 mmol). The reactionwas heated to 55° C. for 24 hours, cooled to room temperature, andquenched with water. The reaction was extracted with DCM (2×75 ml), andthe combined organic fractions were dried over Na₂SO₄, filtered, andconcentrated. The resulting oil was purified by column chromatography(DCM-MeOH=100:1) to give the title compound (0.60 g, 68%). MS: Calcd.:374. Found: [M+H]⁺ 375.

Method 48-52

Following a similar procedure to Method 47, the following compounds weresynthesized from a nitropyridine by reacting it with a pyrazole amine.

Method Product NMR/MS Amine SM 48 N²-(5-Cyclopropyl- MS: Calcd.: 386;Found: 5- Method 1H-pyrazol-3-yl)-3- [M + H]⁺ 387. cyclopropyl- 54fluoro-N⁶-(4- 1H- fluorobenzyl)-5- pyrazol-3- nitropyridine-2,6- aminediamine 49 (R)-2-(6-(5- δ 10.84 (s, 1H), 8.02 (d, J = 10.7 Hz, 5- MethodCyclopropyl-1H- 1H), 7.35-7.31 (m, 2H), cyclopropyl- 55 pyrazol-3-7.10-7.06 (m, 2H), 6.21-6.19 (m, 1H- ylamino)-5-fluoro- 1H), 5.80 (br s,1H), 4.07 (dd, J = 11.3 pyrazol-3- 3-nitropyridin-2- and 3.9 Hz, 1H),3.99 (dd, amine ylamino)-2-(4- J = 11.3 and 6.4 Hz, 1H),fluorophenyl)ethanol 1.88-1.86 (m, 1H), 1.62 (br s, 1H), 0.98-0.95 (m,2H), 0.70-0.68 (m, 2H). MS: Calcd.: 416; Found: [M + H]⁺ 417. 50(S)—N²-(5- (400 MHz, CD₃OD) δ 8.00 (d, J = 11.1 Hz, 5- MethodCyclopropyl-1H- 1H), 7.38-7.35 (m, cyclopropyl- 53 pyrazol-3-yl)-3- 2H),7.07-7.02 (m, 2H), 6.17 (s, 1H- fluoro-N⁶-(1-(4- 1H), 5.41-5.39 (m, 1H),pyrazol-3- fluorophenyl)ethyl)- 1.93-1.87 (m, 1H), 1.61 (d, J = 7.0 Hz,amine 5-nitropyridine- 3H), 1.02-1.00 (m, 2H), 2,6-diamine 0.69-0.66 (m,2H). MS: Calcd.: 400; Found: [M + H]⁺ 401. 51 (S)-3-Fluoro-N⁶-(1- (400MHz, CD₃OD) δ 8.00 (d, J = 10.9 Hz, 5- Method (4-fluorophenyl)ethyl)-1H), 7.45-7.35 (m, isopropoxy- 53 N²-(5- 2H), 7.07-7.03 (m, 2H),1H-pyrazol- isopropoxy-1H- 5.88-5.71 (m, 1H), 5.48-5.30 (m, 1H), 3-aminepyrazol-3-yl)-5- 4.58-4.29 (m, 1H), 1.68-1.56 (m, nitropyridine-2,6-3H), 1.34-1.28 (m, 6H). MS: diamine Calcd.: 418; Found: [M + H]⁺ 419. 52(R)-2-(5-Fluoro-6- δ 10.85 (br s, 1H), 8.02 (d, J = 10.5 Hz, 5-methyl-Method (5-methyl-1H- 1H), 7.34-7.31 (m, 2H), 1H-pyrazol- 54 pyrazol-3-7.10-7.06 (m, 2H), 6.26-6.25 (m, 3-amine ylamino)-3-nitro 1H), 5.86 (brs, 1H), pyridin-2-ylamino)- 5.30-5.27 (m, 1H), 4.07 (dd, J = 11.3 and2-(4-fluorophenyl)ethanol 3.9 Hz, 1H), 3.97 (dd, J = 11.1 and 6.2 Hz,1H), 2.27 (s, 3H), 1.61 (br s, 1H). MS: Calcd.: 390; Found: [M + H]⁺391.Method 53

(S)-5,6-Difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine

A solution of 2,3,6-trifluoro-5-nitropyridine (Method 56, 2.0 g, 11.2mmol) in THF (50 ml) was cooled to 0° C., to which was added(S)-1-(4-fluorophenyl)ethanamine (1.56 g, 11.2 mmol). The reaction wasstirred at 0° C. for 30 min., then quenched with water (50 ml) andextracted with DCM (2×75 ml). The combined organic fractions were driedover Na₂SO₄, filtered, and then concentrated. The resulting oil waspurified by column chromatography (hexanes-DCM=1:1) to give the titlecompound (2.3 g, 70%).

Method 54-55

Following a similar procedure to Method 53, the following compounds weresynthesized from 2,3,6-trifluoro-5-nitropyridine by reacting it with anamine.

Method Product NMR/MS Amine 54 5,6-Difluoro-N-(4- MS: Calcd.: 283; (4-fluorobenzyl)-3- Found: [M + H]⁺ fluorophenyl)- nitropyridin-2-amine284. methanamine 55 (R)-2-(5,6-Difluoro-3- MS: Calcd.: 313;(R)-2-Amino-2-(4- nitropyridin-2- Found: [M + H]⁺ fluorophenyl)-ylamino)-2-(4- 314. ethanol fluorophenyl)ethanolMethod 56

2,3,6-Trifluoro-5-nitropyridine

To neat 2,3,6-trifluoropyridine (12.0 g, 90 mmol) was slowly addedfuming HNO₃ (142 g, 2254 mmol) and H₂SO₄ (133 g, 1353 mmol) slow enoughto keep the internal temperature below 40° C. Upon completion of theaddition, the resulting solution was heated to 60° C. for 30 minutes,and then cooled to 0° C. Ice water (2 L) was then added, and thereaction mixture was extracted with hexanes (2×300 ml) and then DCM(1×300 ml). The combined organic fractions were dried over Na₂SO₄,filtered, and concentrated to give the title compound (8.1 g, 50%),which was used without further purification.

Method 57

(S)-5-Chloro-N²-(1-(4-fluorophenyl)ethyl)pyridine-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-2,3,6-triamine

A solution of saturated ammonium chloride (3 ml) was added slowly to asuspension of(S)-3-chloro-N⁶-(1-(4-fluorophenyl)ethyl)-N²-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine(Method 58, 0.32 g, 0.74 mmol) and zinc dust (0.24 g, 3.7 mmol) inMeOH-THF (1:1, 20 ml). The mixture was stirred at 25° C. for 1 hour.Saturated ammonium acetate solution (5 ml) was added and the mixture wasstirred for another 30 minutes. Zn dust was removed by filtration andthe cake was washed with EtOAc (20 ml). The organic layer was separated,washed with brine (10 ml), and dried over sodium sulfate. After removalof solvent, the title compound was obtained which was used directly forthe next step without purification. MS: Calcd.: 404. Found: [M+H]⁺ 405.

Method 58

(S)-3-Chloro-N⁶-(1-(4-fluorophenyl)ethyl)-N²-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine

A mixture of3,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine(Method 59, 0.25 g, 0.75 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.13g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heatedin a sealed tube at 145° C. for 2 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatography(hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g,98%). ¹H NMR (400 MHz) δ 12.22 & 11.40 (s, 1H), 9.74 & 9.37 (s, 1H),8.93 (d, J=7.6 Hz, 1H), 8.33 & 8.27 (s, 1H), 7.34 & 7.27 (m, 2H), 7.12 &7.05 (m, 2H), 5.75 & 5.62 (s, 1H), 5.35 & 5.25 (m, 1H), 4.66 & 4.03 (m,1H), 1.55 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 434.Found: [M+H]⁺ 435.

Method 59

3,6-Dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine

To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) andDIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. Afteraddition, the reaction mixture was stirred at 25° C. for 5 days. Thesolvent was removed under reduced pressure and the resulted residue waspurified by column chromatography (hexane-EtOAc=1:1) to give the titlecompound as a yellow solid (0.51 g, 18%). ¹H NMR (400 MHz) δ 12.22 &11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84(s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found:[M+H]⁺ 332.

Method 60

(S)—N²-(1-(4-Fluorophenyl)ethyl)pyridine-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-2,3,6-triamine

A solution of saturated ammonium chloride (3 ml) was added slowly to asuspension of(S)—N²-(1-(4-fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine(Method 61, 0.28 g, 0.70 mmol) and zinc dust (0.23 g, 3.5 mmol) in themixture of MeOH-THF (1:1, 20 ml). The mixture was stirred at 25° C. for1 hour. Saturated ammonium acetate solution (5 ml) was added and themixture was stirred for another 30 minutes. Zn dust was removed byfiltration and the cake was washed with EtOAc (20 ml). The organic layerwas separated, washed with brine (10 ml), and dried over sodium sulfate.After removal of solvent, the title compound was obtained which was useddirectly for the next step without purification. MS: Calcd.: 370. Found:[M+H]⁺ 371.

Method 61

(S)—N²-(1-(4-Fluorophenyl)ethyl)-N⁶-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridine-2,6-diamine

A mixture of(S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method19, 1.08 g, 3.7 mmol), 5-isopropoxy-1H-pyrazol-3-amine (0.57 g, 4.0mmol), and DIEA (0.80 ml, 4.6 mmol) in n-BuOH (10 ml) was heated in asealed tube at 115° C. for 72 hours. The solvent was removed underreduced pressure and the residue was purified by chromatography(hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.32 g,22%). MS: Calcd.: 400. Found: [M+H]⁺ 401.

Method 62

(R)-2-(3-Amino-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

A solution of saturated ammonium chloride (3 ml) was added slowly to asuspension of(R)-2-(4-fluorophenyl)-2-(6-(5-methyl-1H-pyrazol-3-ylamino)-3-nitropyridin-2-ylamino)ethanol(Method 63, 0.29 g, 0.78 mmol) and zinc dust (0.25 g, 3.9 mmol) in amixture of MeOH-THF (1:1, 20 ml). The mixture was stirred at 25° C. for1 hour. Saturated ammonium acetate solution (5 ml) was added and themixture was stirred for another 30 minutes. The Zn dust was removed byfiltration and the cake was washed with EtOAc (20 ml). The organic layerwas separated, washed with brine (10 ml) and dried over sodium sulfate.After removal of solvent, the title compound was obtained which was useddirectly for the next step without purification. MS: Calcd.: 342. Found:[M+H]⁺ 343.

Method 63

(R)-2-(4-Fluorophenyl)-2-(6-(5-methyl-1H-pyrazol-3-ylamino)-3-nitropyridin-2-ylamino)ethanol

A mixture of(2R)-2-(6-chloro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol(Method 21, 0.36 g, 1.2 mmol), 5-methyl-1H-pyrazol-3-amine (0.14 g, 1.4mmol), and DIEA (0.25 ml, 1.4 mmol) in n-BuOH (5 ml) was heated in asealed tube at 90° C. for 6 days. The solvent was removed under reducedpressure and the residue was purified by column chromatography (EtOAc)to give the title compound as a yellow solid (0.31 g, 73%). ¹H NMR (400MHz) δ 12.06 (s, 1H), 10.40 (br s, 1H), 9.58 (br s, 1H), 8.11 (d, J=9.2Hz, 1H), 7.40 (m, 2H), 7.16 (m, 2H), 6.20 (br s, 1H), 6.02 (s, 1H), 5.29(br, 1H), 5.24 (t, J=4.4 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 2.20 (s,3H). MS: Calcd.: 372. Found: [M+H]⁺ 373.

Utility

The compounds of the present invention have utility for the treatment ofcancer by inhibiting the tyrosine kinases, particularly the Trks andmore particularly Trk A and B. Methods of treatment target tyrosinekinase activity, particularly the Trk activity and more particularly TrkA and B activity, which is involved in a variety of cancer relatedprocesses. Thus, inhibitors of tyrosine kinase, particularly the Trksand more particularly Trk A and B, are expected to be active againstneoplastic disease such as carcinoma of the breast, ovary, lung, colon,prostate or other tissues, as well as leukemias and lymphomas, tumoursof the central and peripheral nervous system, and other tumour typessuch as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinaseinhibitors, particularly the Trk inhibitors and more particularly Trk Aand B inhibitors are also expected to be useful for the treatment otherproliferative diseases including but not limited to autoimmune,inflammatory, neurological, and cardiovascular diseases.

In addition, the compounds of the invention are expected to be of valuein the treatment or prophylaxis of cancers selected with up regulated ofconstitutively activated Trk kinases, including but not limited to,oncogenic rearrangements leading to ETV6-TrkC fusions, TRP-TrkA fusionsproteins, AML-ETO (t8;21), autocrine or paracrine signalling leading toelevated serum levels of NGF, BDNF, neurotropins or tumours withconstitutively active Trk associated with disease aggressiveness, tumourgrowth and proliferation or survival signalling.

Compounds of the present invention have been shown to inhibit tyrosinekinases, particularly the Trks and more particularly Trk A and B, asdetermined by the Trk A Assay described herein.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit tyrosine kinases, particularly the Trks and more particularlyTrk A and B. These would be provided in commercial kits comprising acompound of this invention

Trk A Assay Format

Trk A kinase activity was measured for its ability to phosphorylatesynthetic tyrosine residues within a generic polypeptide substrate usingan Amplified Luminescent Proximity Assay (Alphascreen) technology(PerkinElmer, 549 Albany Street, Boston, Mass.).

To measure Trk A kinase activity, the intracellular domain of aHIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-ProtPrimary Accession Number P04629) was expressed in SF9 cells and purifiedusing standard nickel column chromatography. After incubation of thekinase with a biotinylated substrate and adenosine triphosphate (ATP)for 20 minutes at room temperature, the kinase reaction was stopped bythe addition of 30 mM ethylenediaminetetraacetic acid (EDTA). Thereaction was performed in 384 well microtitre plates and the reactionproducts were detected with the addition of strepavidin coated DonorBeads and phosphotyrosine-specific antibodies coated Acceptor Beadsusing the EnVision Multilabel Plate Reader after an overnight incubationat room temperature.

Peptide PolyEY-biotin (PGT-bio.) substrate ATP Km 70 μM Assay 0.838ng/ml Trk A, 9 mM HEPES, 45 μg/ml BSA, 10 mM conditions MnCl₂, 5 nMPGT-bio, 0.01% Triton ® X-100, 70 μM ATP Incubation 20 minutes, roomtemperature Termination/ 6.3 mM HEPES, 30 mM EDTA, 525 μg/mL BSA, 40 mMDetection NaCl, 0.007% Triton ® X-100, 12 ng/ml of Donor Beads,conditions 12 ng/ml of Acceptor Beads Detection overnight, roomtemperature incubation Fluometers Excitation = 680 nM Emission = 570 nMExcitation settings Time = 180 ms Total Measurement Time = 550 ms

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) may be demonstrated at IC₅₀ concentrations(concentrations to achieve 50% inhibition) or doses in the range of(0.01 μM to 10 μM).

When tested in the above in-vitro assay the Trk inhibitory activity ofthe following examples was measured at the following IC₅₀s.

Ex IC₅₀ (μM) 5 0.063 6 0.049 18 0.011

1. A compound of formula (I):

wherein: R¹ and R² are independently selected from hydrogen, halo,nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R¹ and R²independently of each other may be optionally substituted on carbon byone or more R⁷; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from R⁸;X¹, X² and X³ are independently ═N— or ═CR⁹—; R³ and R⁹ areindependently selected from hydrogen, halo, nitro, cyano, hydroxy,trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino,C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R¹⁰— or heterocyclyl-R¹¹; whereinR³ and R₉ independently of each other may be optionally substituted oncarbon by one or more R¹²; and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a groupselected from R¹³; R⁴ and R⁵ are independently selected from hydrogen,halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R⁴ and R⁵independently of each other may be optionally substituted on carbon byone or more R¹⁴; and wherein if said heterocyclyl contains an —NH—moiety that nitrogen may be optionally substituted by a group selectedfrom R¹⁵; A is a direct bond or C₁₋₂alkylene; wherein said C₁₋₂alkylenemay be optionally substituted by one or more Ring C is carbocyclyl orheterocyclyl; wherein if said heterocyclyl contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from R¹⁷; R⁶is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R⁶ may be optionally substituted on carbon by oneor more R¹⁸; and wherein if said heterocyclyl contains an —NH— moietythat nitrogen may be optionally substituted by a group selected fromR¹⁹; n is 0, 1, 2 or 3; wherein the values of R⁶ may be the same ordifferent; R⁷, R¹², R¹⁴, R¹⁶ and R¹⁸ and are independently selected fromhalo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino, carbocyclyl-R²⁰— or heterocyclyl-R²¹—; whereinR⁷, R¹², R¹⁴, R¹⁶ and R¹⁸ independently of each other may be optionallysubstituted on carbon by one or more R²²; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²³; R⁸, R¹³, R¹⁵, R¹⁷, R¹⁹ and R²³are independently selected from C₁₋₆alkyl, C₁₋₆alkanoyl,C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R⁸, R¹³, R¹⁵,R¹⁷, R¹⁹ and R²³ independently of each other may be optionallysubstituted on carbon by on or more R²² and R²⁴ are independentlyselected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino, carbocyclyl orheterocyclyl; wherein R²² and R²⁴ independently of each other may beoptionally substituted on carbon by one or more R²⁵; and wherein if saidheterocyclyl contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from R²⁶; R¹⁰, R¹¹, R²⁰ and R²¹ areindependently selected from a direct bond, —O—, —N(R²⁷)—, —C(O)—,—N(R²⁸)C(O)—, —C(O)N(R²⁹)—, —S(O)—, —SO₂N(R³⁰)— or —N(R³¹)SO₂—; whereinR²⁷, R²⁸R²⁹, R³⁰ and R³¹ are independently selected from hydrogen orC₁₋₆alkyl and s is 0-2; R²⁵ is selected from halo, nitro, cyano,hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl,mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,methylamino, ethylamino, dimethylamino, diethylamino,N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl,ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl,N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl orN-methyl-N-ethylsulphamoyl; and R²⁶ is selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy or carbocyclyl.
 3. A compoundof formula (I), or a pharmaceutically acceptable salt thereof, asclaimed in claim 1 wherein R² is hydrogen.
 4. A compound of formula (I),or a pharmaceutically acceptable salt thereof, as claimed claim 1wherein R³ and R⁹ are independently selected from hydrogen, halo,hydroxy and C₁₋₆alkyl.
 5. A compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR⁴ and R⁵ are independently selected from hydrogen or C₁₋₆alkyl; andwherein R⁴ and R⁵ independently of each other may be optionallysubstituted on carbon by one or more R¹⁴; wherein R¹⁴ is hydroxy.
 6. Acompound of formula (I), or a pharmaceutically acceptable salt thereof,as claimed in claim 1 wherein A is a direct bond.
 7. A compound offormula (I), or a pharmaceutically acceptable salt thereof, as claimedin claim 1 wherein Ring C is phenyl.
 8. A compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1 whereinR⁶ is halo.
 9. A compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as claimed in claim 1 wherein n is 0 or
 1. 10.A compound of formula (I):

wherein: R¹ is selected from methyl, t-butyl, isopropoxy or cyclopropyl;R² is hydrogen; X¹, X² and X³ are independently ═N— or ═CR⁹—; R³ and R²are independently selected from hydrogen, fluoro, chloro, hydroxy andmethyl; R⁴ and R⁵ are independently selected from hydrogen, methyl orhydroxymethyl; A is a direct bond; Ring C is phenyl; R⁶ is fluoro; and nis 1; or a pharmaceutically acceptable salt thereof.
 11. A compound offormula (I):

selected from:(S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine;(R)-2-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-2-(4-fluorophenyl)ethanol;(S)-6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-(1-(4-fluorophenyl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine;(R)-2-(6-chloro-5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-2-(4-fluorophenyl)ethanol;(R)-2-(6-chloro-5-(5-methyl-1H-pyrazol-3-ylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-2-(4-fluorophenyl)ethanol;(S)-6-fluoro-3-(1-(4-fluorophenyl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine;(R)-2-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)-2-(4-fluorophenyl)ethanol;(S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-fluoro-3-(1-(4-fluorophenyl)ethyl)-3H-imidazo[4,5-b]pyridin-5-amine;(S)-6-fluoro-3-(1-(4-fluorophenyl)ethyl)-N-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine;and(S)-6-chloro-3-(1-(4-fluorophenyl)ethyl)-N-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine;or a pharmaceutically acceptable salt thereof.
 12. A process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof which process, wherein variable groups are, unlessotherwise specified, as defined in claim 1, wherein said process isselected from: Process a) reaction of a compound of formula (II):

wherein Pg is a nitrogen protecting group; with a compound of formula(III):

wherein L is a displaceable group to produce a compound of formula (I);Process b) reaction of a compound of formula (II) with an epoxide offormula (IV) to produce a compound of formula (I) wherein R⁴ ishydroxymethyl and R⁵ is hydrogen:

Process c) reacting a compound of formula (V):

with a compound of formula (VI) to produce a compound of formula (I)wherein X¹ is ═CR⁹—:

Process d) reacting a compound of formula (V) with aqueous NaNO₂solution to produce a compound of formula (I) wherein X¹ is ═N—; Processe) reacting a compound of formula (VII):

wherein L is a displaceable group; with an amine of formula (VIII):

wherein Pg is a nitrogen protecting group to produce a compound offormula (I); Process f) reacting a compound of formula (IX):

with a compound of formula (X):

wherein L is a displaceable group to produce a compound of formula (I);and thereafter if necessary: i) converting a compound of the formula (I)into another compound of the formula (I); ii) removing any protectinggroups; iii) forming a pharmaceutically acceptable salt.
 13. Apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed in claim 1,together with at least one pharmaceutically acceptable carrier, diluentor excipient.